The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
In drug delivery, the “burst effect” or “burst release”, in which a large amount of a drug is quickly released (and typically immediately upon placement into release medium) from a pharmaceutical formulation (typically consisting of a drug or an active pharmaceutical ingredient (API) and a matrix material with optional additives), is mostly considered to be harmful, even dangerous if the concentration of a drug in the body would increase too much. If the pharmaceutical formulation is in the form of a device and the released amount in the burst is high, it may also reduce the lifetime of the device remarkably. However, if the ratio between the drug released in the burst and the total amount of the drug is low, and the burst can be controlled by the formulation, the burst may also be beneficial. For treatment of some diseases it may better to have higher drug concentrations in the beginning of the treatment, which should be followed by a controlled and sustained release. However, a controlled burst in the beginning of the medication is not often needed, because in the beginning of a treatment, e.g., while implanting or injecting the release-controlling pharmaceutical formulation, it is relatively easy to give a certain amount of a drug also orally or by injecting a suitable amount of a drug solution. Thus, in most cases the burst is to be avoided instead a controlled and sustained release is desired from the very beginning, and most preferably a zero order release.
The key question is that the burst effect should be controlled. If the burst is not desired, there should be a method to avoid or minimize it. There are various materials and methods (e.g., coatings, membranes, pore size modifications, reservoir structures with different outer layer properties, chemical surface modifications, surface erosion-controlled biodegradation) developed to control it, because there are several reasons for the burst. The burst may depend, e.g., on the drug properties (e.g., a highly water-soluble drug may be released fast from a matrix that otherwise controls very well a less water-soluble drug), the typical matrix pore structure may be more beneficial for certain size classes of drugs (e.g., for macromolecules such as proteins), the (pore) surface of the matrix or a membrane may have different interaction forces with different drugs, and the preparation process (e.g., methods with sudden phase transformations such as spray-drying) of the formulation may typically result in a structure, where a certain, and relatively large amount (larger than the average in the matrix) of a drug is often located near the outer surface of the matrix material.
The burst is more difficult to control when the encapsulated molecule is highly water-soluble and it becomes somewhat easier for larger molecules and other large agents, e.g., viral vector, but the burst depends often also on the drug loading in a pharmaceutical formulation, i.e. a high weight ratio between a drug and a matrix material controlling the release. It is obvious in most cases that the lower the drug concentration the easier it is to control the burst and sustained release. Lower drug concentrations do not affect the (formation of) matrix structure so much and also the accumulation of a large amount of a drug near the outer surface of the matrix material is less probable. However, the high drug loading capability is often desired, because it provides flexibility in the product development and it is easier to develop controlled release matrices also for less potent drugs. The high drug loading enables also smaller size for controlled delivery systems, e.g., smaller implant or a smaller volume and dry content in an injectable system. The reduced size or amount is preferable because the administration is easier and it also improves the patient compliance.
Materials and methods for burst control are often drug-dependent and there is a need for a more general solution that would fit several different active pharmaceutical ingredients (API) and other therapeutic and biologically active agents. Hydrogels are potential solutions when combined with other morphologies, e.g., with particles of different size such as nanoparticles or microparticles. The resulting structures can be adjusted to be injectable with thin needles to obtain minimally invasive administration solutions. If the interaction between the particles and the hydrogel is strong enough or if the combined structure otherwise results in a unique structure, it may in the best case result in a structure that controls the release (whole release and/or burst) of API and other therapeutic and biologically active agents independently on the encapsulated agent, e.g., independent of the water solubility, hydrophobicity or other properties. Although the release would not totally be independent of the properties of API or other therapeutic and biologically active agents, the combined structure of particles and hydrogels may still have a major impact on the release kinetics and may solve problems, such as too fast burst in the beginning of the release.
US2009/0324695 by Ducheyne and Devore discloses a combination of organic hydrogels and silica microparticles in the adjustment of drug release kinetics and in controlling burst. They disclose a material that turns into a hydrogel when used (e.g., when placed into contact with tissue and the fluids of the tissue), i.e., the disclosed product is not a hydrogel. The weight ratio between the polymer used to prepare the hydrogel and silica varies between 5-95%.
Holland et al. (Journal of Controlled Release, 91 (3), p. 299-313, 2003; Journal of Controlled Release, 94 (1), p. 101-114, 2004; Journal of Controlled Release, 101 (1-3), p. 111-125, 2005 and Biomaterials, 26 (34), p. 7095-7103, 2005) have combined organic microparticles and organic polymers to prepare an injectable formulation. They have focused on a large encapsulated agents (growth factor proteins that are macromolecules) and they have combined organic materials (gelatine microparticles and oligo(poly(ethylene glycol) fumarate, OPF). The combined composition of gelatine microparticles and OPF reduced the burst of growth factors, but either increased or decreased the overall release rate of the growth factors when compared with the gelatin microparticles as such.
Shoichet et al. (Journal of Controlled Release, 160, p. 666-675, 2012 and Journal of Controlled Release, 166, p. 197-202, 2013) combined organic PLGA nanoparticles with organic hyaluronan (1 wt-%, 2600 kDa) and methyl cellulose (3 wt-%, 300 kDa) (HAMC) or organic PEG-400 to form composite formulations (whether they are injectable or not is not mentioned). The combination affected both the burst and the overall release when compared with the particles as such.
Shien and Burgess (International Journal of Pharmaceutics, 422, p. 341-348, 2012) have combined organic PLGA microparticles with an organic PVA hydrogel. They prepared and implantable device (after hydrogel formation, several freezing-thawing cycles were conducted) and they did not compare the release properties to the PLGA microparticles as such. Hence, no benefit of the combination was shown, not on the burst or on the overall release.
Wang et al. (Biomaterials, 31, p. 4955-4951, 2010) have combined organic nanospheres (HEMA-DEAMEA-EGDMA) with an organic hydrogel (HEMA-MPC-TMPTA-PEGDA) to prepare an implantable material (the hydrogel was freeze-dried into an implant). The composite did not affect the burst, but reduced the overall release rate.
Gupta et al. have prepared an injectable, shear-thinning hydrogel out of blends of hyaluronan and methylcellulose (HAMC).